Molecular Cancer Research最新文献

{"title":"The Role of WDR77 in Cancer: More than a PRMT5 Interactor.","authors":"Isaac Silverman, Aaron Shaykevich, Radhashree Maitra","doi":"10.1158/1541-7786.MCR-24-0933","DOIUrl":"10.1158/1541-7786.MCR-24-0933","url":null,"abstract":"<p><p>WD repeat domain 77 protein (WDR77), a WD-40 domain-containing protein, is a crucial regulator of cellular pathways in cancer progression. Although much of the past research on WDR77 has focused on its interaction with protein arginine methyltransferase 5 (PRMT5) in histone methylation, WDR77's regulatory functions extend beyond this pathway, influencing diverse mechanisms such as mRNA translation, chromatin assembly, cell-cycle regulation, and apoptosis. WDR77 is a key regulator of cell-cycle progression, regulating the transition from the G1 phase. WDR77 regulates many signaling pathways such as TGFβ in which its role in these cellular pathways underscores its broad oncogenic potential. WDR77 also assists and promotes certain transcription factors such as E2F. Furthermore, in certain cancers, WDR77 enhances steroid hormone receptor activity, uniquely linking it to hormone-driven malignancies. WDR77 often translocates between the nucleus and the cytoplasm, with its location dictating its role in the cell. WDR77 has the ability to adapt its function depending on its location that emphasizes its dynamic role in both promoting and inhibiting tumor growth, depending on cellular context. This dual function makes WDR77 an attractive therapeutic target, as disrupting its interactions with critical signaling pathways or modulating its translocation could yield novel strategies for cancer treatment. Given WDR77's role in oncogenic pathways independent of PRMT5, further exploration of WDR77 and its non-PRMT5-related activities may reveal additional therapeutic opportunities in an array of cancers.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"269-276"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143033758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coevolution of Atypical BRAF and KRAS Mutations in Colorectal Tumorigenesis.","authors":"Connor E Woolley, Enric Domingo, Juan Fernandez-Tajes, Kathryn A F Pennel, Patricia Roxburgh, Joanne Edwards, Susan D Richman, Tim S Maughan, David J Kerr, Ignacio Soriano, Ian P M Tomlinson","doi":"10.1158/1541-7786.MCR-24-0464","DOIUrl":"10.1158/1541-7786.MCR-24-0464","url":null,"abstract":"<p><p>BRAF mutations in colorectal cancer comprise three functional classes: class 1 (V600E) with strong constitutive activation, class 2 with pathogenic kinase activity lower than that of class 1, and class 3 which paradoxically lacks kinase activity. Non-class 1 mutations associate with better prognosis, microsatellite stability, distal tumor location, and better anti-EGFR response. An analysis of 13 colorectal cancer cohorts (n = 6,605 tumors) compared class 1 (n = 709, 10.7% of colorectal cancers), class 2 (n = 31, 0.47%), and class 3 (n = 81, 1.22%) mutations. Class 2-mutant and class 3-mutant colorectal cancers frequently co-occurred with additional Ras pathway mutations (29.0% and 45.7%, respectively, vs. 2.40% in class 1; P < 0.001), often at atypical sites (KRAS noncodon 12/13/61, NRAS, or NF1). Ras pathway activation was highest in class 1 and lowest in class 3, with a greater distal expression of EGFR ligands (amphiregulin/epiregulin) supporting weaker BRAF driver mutations. Unlike class 1 mutants, class 3 tumors resembled chromosomally unstable colorectal cancers in mutation burdens, signatures, driver mutations, and transcriptional subtypes, whereas class 2 mutants displayed intermediate characteristics. Atypical BRAF mutations were associated with longer overall survival than class 1 mutations (HR = 0.25; P = 0.011) but lost this advantage in cancers with additional Ras mutations (HR = 0.94; P = 0.86). This study supports the suggestion that class 3 BRAF mutations amplify existing Ras signaling in a two-mutation model and that the enhancement of weak/atypical Ras mutations may suffice for tumorigenesis, with potentially clinically important heterogeneity in the class 2/3 subgroup. Implications: The heterogeneous nature of BRAF-mutant colorectal cancers, particularly among class 2/3 mutations which frequently harbor additional Ras mutations, highlights the necessity of comprehensive molecular profiling.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"300-312"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7617415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142922372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor Microenvironment: Obstacles and Opportunities for T Cell-Based Tumor Immunotherapies.","authors":"Miao-Miao Hu, Ying Zhao, Nan Zhang, Fang-Yuan Gong, Wei Zhang, Chun-Sheng Dong, Jian-Feng Dai, Jun Wang","doi":"10.1158/1541-7786.MCR-24-0747","DOIUrl":"10.1158/1541-7786.MCR-24-0747","url":null,"abstract":"<p><p>The complex composition and dynamic change of the tumor microenvironment (TME), mainly consisting of tumor cells, immune cells, stromal cells, and extracellular components, significantly impede the effector function of cytotoxic T lymphocytes (CTL), thus representing a major obstacle for tumor immunotherapies. In this review, we summarize and discuss the impacts and underlying mechanisms of major elements in the TME (different cell types, extracellular matrix, nutrients and metabolites, etc.) on the infiltration, survival, and effector functions of T cells, mainly CD8+ CTLs. Moreover, we also highlight recent advances that may potentiate endogenous antitumor immunity and improve the efficacy of T cell-based immunotherapies in patients with cancer by manipulating components inside/outside of the TME. A deeper understanding of the effects and action mechanisms of TME components on the tumor-eradicating ability of CTLs may pave the way for discovering new targets to augment endogenous antitumor immunity and for designing combinational therapeutic regimens to enhance the efficacy of tumor immunotherapies in the clinic.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"277-287"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bmal1-Mediated Circadian MELK Expression Potentiates MELK Inhibitor Chronotherapy for Esophageal Cancer.","authors":"Boning Zeng, Chao Sun, Qian Tang, Nan Li, Siying Chen, Yili Yang, Xiao Wang, Shaoxiang Wang","doi":"10.1158/1541-7786.MCR-24-0498","DOIUrl":"10.1158/1541-7786.MCR-24-0498","url":null,"abstract":"<p><p>Esophageal squamous cell carcinoma (ESCC) remains a global health challenge. Circadian clock and maternal embryonic leucine zipper kinase (MELK) play a key role in tumorigenesis. However, a link between circadian clock dysregulation and MELK function in the occurrence and development of ESCC remains elusive. Here, In the in vivo and in vitro systems, we found for the first time that MELK exhibits pronounced circadian rhythms expression in mice esophageal tissue, xenograft model, and human ESCC cells. The diurnal differences expression between peak (ZT0) and trough (ZT12) points in normal esophageal tissue is nearly 10-fold. Circadian expression of MELK in ESCC cells was regulated by Bmal1 through binding to the MELK promoter. Supporting this, the levels of MELK were increased significantly in patients with ESCC and were accompanied by altered expression of core clock genes, especially, since Bmal1 is prominently upregulated. Most importantly, Bmal1-deleted eliminated the rhythmic expression of MELK, whereas the knockdown of other core genes had no effect on MELK expression. Furthermore, in nude mice with transplanted tumors, the anticancer effect of OTS167 at ZT0 administration is twice that of ZT12. Implications: Our findings suggest that MELK represents a therapeutic target, and can as a regulator of circadian control ESCC growth, with these findings advance our understanding of the clinical potential of chronotherapy and the importance of time-based MELK inhibition in cancer treatment.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"288-299"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lysosomal-Mitochondrial Interaction Promotes Tumor Growth in Squamous Cell Carcinoma of the Head and Neck.","authors":"Avani Gopalkrishnan, Nathaniel Wang, Silvia Cruz-Rangel, Abdul Yassin-Kassab, Sruti Shiva, Chareeni Kurukulasuriya, Satdarshan P Monga, Ralph J DeBerardinis, Heath D Skinner, Kirill Kiselyov, Umamaheswar Duvvuri","doi":"10.1158/1541-7786.MCR-24-0337","DOIUrl":"10.1158/1541-7786.MCR-24-0337","url":null,"abstract":"<p><p>Communication between intracellular organelles including lysosomes and mitochondria has recently been shown to regulate cellular proliferation and fitness. The way lysosomes and mitochondria communicate with each other [lysosomal-mitochondrial interaction (LMI)] is emerging as a major determinant of tumor proliferation and growth. About 30% of squamous carcinomas [including squamous cell carcinoma of the head and neck (SCCHN)] overexpress transmembrane member 16A (TMEM16A), a calcium-activated chloride channel, which promotes cellular growth and negatively correlates with patient survival. We have recently shown that TMEM16A drives lysosomal biogenesis; however, its impact on mitochondrial function has not been explored. In this study, we show that in the context of high-TMEM16A SCCHN, (i) patients display increased mitochondrial content, specifically complex I; (ii) in vitro and in vivo models uniquely depend on mitochondrial complex I activity for growth and survival; (iii) NRF2 signaling is a critical linchpin that drives mitochondrial function, and (iv) mitochondrial complex I and lysosomal function are codependent for proliferation. Taken together, our data demonstrate that coordinated lysosomal and mitochondrial activity and biogenesis via LMI drive tumor proliferation and facilitate a functional interaction between lysosomal and mitochondrial networks. Therefore, inhibition of LMI instauration may serve as a therapeutic strategy for patients with SCCHN. Implications: Intervention of LMI may serve as a therapeutic approach for patients with high TMEM16A-expressing SCCHN.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"339-349"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring B7-H4's Role in Prostate Cancer Dormancy after Androgen Deprivation Therapy: Extracellular Matrix Interactions and Therapeutic Opportunities.","authors":"Ning Kang, Hui Xue, Nelson K Y Wong, Yen-Yi Lin, Adam Classen, Rebecca Wu, Htoo Zarni Oo, Xin Dong, Angela Trinh, Dong Lin, Mads Daugaard, Christopher Ong, Colin Collins, Martin Gleave, Yuzhuo Wang","doi":"10.1158/1541-7786.MCR-24-0958","DOIUrl":"10.1158/1541-7786.MCR-24-0958","url":null,"abstract":"<p><p>Prostate cancer is mainly managed with androgen deprivation therapy (ADT), but this often leads to a dormant state and subsequent relapse as lethal castration-resistant prostate cancer (CRPC). Using our unique prostate cancer patient-derived xenograft dormancy models, we investigated this critical dormant phase and discovered a selective increase in B7-H4 expression during the dormancy period following mouse host castration. This finding is supported by observations in clinical specimens of patients with prostate cancer treated with ADT. Differential expression analyses revealed the enrichment of extracellular matrix (ECM)-cell interaction pathways in B7-H4-positive cells. Functional assays demonstrated a crucial role of B7-H4 in maintaining dormancy within the ECM niche. Specifically, B7-H4 expression in LNCaP cells reduced proliferation within the dormant ECM in vitro and significantly delayed relapse in castrated hosts in vivo. These results shed light on the dynamic regulation of B7-H4 during prostate cancer dormancy and underscore its potential as a therapeutic target for preventing CRPC relapse. Implications: Our study identified membranous B7-H4 expression during ADT-induced dormancy, highlighting its potential as a therapeutic target for managing dormant prostate cancer and preventing fatal CRPC relapse.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"327-338"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11972443/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell and spatial transcriptomics reveal a tumor-associated macrophage subpopulation that mediates prostate cancer progression and metastasis.","authors":"Shenglin Mei, Hanyu Zhang, Taghreed Hirz, Nathan Elias Jeffries, Yanxin Xu, Ninib Baryawno, Shulin Wu, Chin-Lee Wu, Akash Patnaik, Philip J Saylor, David B Sykes, Douglas M Dahl","doi":"10.1158/1541-7786.MCR-24-0791","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0791","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs) are a transcriptionally heterogeneous population, and their abundance and function in prostate cancer is poorly defined. We integrated parallel datasets from single-cell RNA-sequencing, spatial transcriptomics and multiplex immunofluorescence to reveal the dynamics of TAMs in primary and metastatic prostate cancer. Four TAM subpopulations were identified. Notably, one of these TAM subsets was defined by the co-expression of SPP1+ and TREM2+ and was significantly enriched in metastatic tumors. The SPP1+/TREM2+ TAMs were enriched in the metastatic tumor microenvironment in both human patient samples and murine models of prostate cancer. The abundance of these SPP1+/TREM2+ macrophages was associated with patient progression free survival. Spatially, TAMs within prostate cancer bone metastases were highly enriched within the tumor region, consistent with their pro-tumorigenic role. Blocking SPP1 in RM1 prostate cancer mouse model led to improved efficacy of anti-PD-1 treatment, and increased CD8 T cell infiltration in tumor. These findings suggest that targeting SPP1+ TAMs may offer a promising therapeutic strategy and potentially enhance the effects of immune checkpoint inhibition (ICI) in advanced prostate cancer. Implications: This study expands our understanding of the diverse roles of macrophage populations in prostate cancer metastases and highlights new therapeutic targets.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Empty spiracles homeobox 2 (EMX2) transcription factor functions as a tumor suppressor in renal cell carcinoma by targeting CADM1.","authors":"Zhibin Fu, Wenqi Chen, Di Gu, Juan Li, Kai Dong, Yuying Lan, Tao Liu, Bianhong Zhang, Lei Li, Ethan Lee, Chenghua Yang, Tao P Zhong, Linhui Wang","doi":"10.1158/1541-7786.MCR-24-0496","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0496","url":null,"abstract":"<p><p>Renal cell carcinoma (RCC), a prevalent urinary system malignancy, often metastasizes at an early stage. Characterized by a complex pathogenesis and high mortality rate, RCC poses a significant clinical challenge. We evaluated the expression level of EMX2 in RCC patients and revealed a significant reduction of EMX2 expression, correlating with poor RCC patient prognosis. EMX2 functions as a tumor suppressor and inhibits RCC cell proliferation and migration, accompanied by programmed cell death. Implantation of EMX2-transduced RCC cells beneath the mouse kidney capsule or subcutaneous injection of transduced RCC cells results in a reduction in tumor growth and size. Through RNA-seq and chromatin immunoprecipitation sequencing analyses, we have identified Cell Adhesion Molecule 1 (CADM1) as a direct transcriptional target of EMX2's suppressive effects. CADM1 induction by EMX2 triggers PARP1-mediated parthanatos, a specific type of cell death due to mitochondrial oxidation reduction, in migrating RCC cells. Concurrently, EMX2-CADM1 upregulation instigates Caspase-3-dependent apoptosis in attached RCC cells. Furthermore, EMX2-CADM1 transcriptional axis also inhibits the PI3K-AKT pathway to impair RCC cell growth. Hence, the orchestrated effects mediated by EMX2-CADM1 axis promote RCC cell death and suppresse its growth and invasion, providing potential intervention strategies for combating RCC. Implications: The EMX2-CADM1 transcriptional axis offers a promising therapeutic target for inducing cell death and inhibiting growth and invasion in renal cell carcinoma, which could lead to more effective treatment strategies for this aggressive malignancy.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KSR2 promotes self-renewal and clonogenicity of small-cell lung carcinoma.","authors":"Dianna H Huisman, Deepan Chatterjee, Robert A Svoboda, Heidi M Vieira, Abbie S Ireland, Sydney Skupa, James W Askew, Danielle E Frodyma, Luc Girard, Kurt W Fisher, Michael S Kareta, John D Minna, Trudy G Oliver, Robert E Lewis","doi":"10.1158/1541-7786.MCR-24-0546","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0546","url":null,"abstract":"<p><p>Small-cell lung carcinoma (SCLC) tumors are heterogeneous, with a subpopulation of cells primed for tumor initiation. Here, we show that Kinase Suppressor of Ras 2 (KSR2) promotes the self-renewal and clonogenicity of SCLC cells. KSR2 is a molecular scaffold that promotes Raf/MEK/ERK signaling. KSR2 is preferentially expressed in the ASCL1 subtype of SCLC (SCLC-A) tumors and is expressed in pulmonary neuroendocrine cells, one of the identified cells of origin for SCLC-A tumors. The expression of KSR2 in SCLC and pulmonary neuroendocrine cells (PNECs) was previously unrecognized and serves as a novel model for understanding the role of KSR2-dependent signaling in normal and malignant tissues. Disruption of KSR2 in SCLC-A cell lines inhibits the colony forming ability of tumor propagating cells (TPCs) in vitro and their tumor initiating capacity in vivo. The effect of KSR2 depletion on self-renewal and clonogenicity is dependent on the interaction of KSR2 with ERK. These data indicate that the expression of KSR2 is an essential driver of SCLC-A tumor propagating cell function, and therefore may play a role in SCLC tumor initiation. These findings shed light on a novel effector promoting initiation of ASCL1-subtype SCLC tumors, and a potential subtype-specific therapeutic target. Implications: Manipulation of the molecular scaffold KSR2 in ASCL1-subtype small-cell lung cancer cells reveals its contribution to self-renewal, clonogenicity, and tumor initiation.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143597417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ANGEL2 modulates wildtype TP53 translation and doxorubicin chemosensitivity in colon cancer.","authors":"Christopher August Lucchesi, Saisamkalpa Mantrala, Darren Tran, Neelu Batra, Avani Durve, Conner Suen, Jin Zhang, Paramita Ghosh, Xinbin Chen","doi":"10.1158/1541-7786.MCR-24-0702","DOIUrl":"10.1158/1541-7786.MCR-24-0702","url":null,"abstract":"<p><p>Multiple lines of correlative evidence support a role for ANGEL2, a novel cancer-relevant RNA-binding protein, in the modulation of chemoresistance and cancer patient survival. However, to date, no study has determined a mechanism by which ANGEL2 modulates cancer progression, nor its role in chemoresistance. Herein, we demonstrate that loss of ANGEL2 leads to a substantial decrease of the key tumor suppressor protein TP53. We show that ANGEL2 directly interacts with EIF4E, the rate limiting protein in cap-dependent translation. This interaction abrogates the ability for the TP53 translation repressor RBM38 to interact with EIF4E thereby enhancing TP53 translation. Loss of ANGEL2 in cancer cell lines resulted in increased 2D and 3D spheroid cell growth, and resistance to doxorubicin and etoposide. With therapeutic potential, treatment with Pep7, a seven amino-acid peptide derived from ANGEL2, rescued wildtype TP53 expression and sensitized cancer cells to doxorubicin. Together, we conclude that ANGEL2 modulates the EIF4E-RBM38 complex to enhance wildtype TP53 translation, and further, the Pep7 peptide may be explored as a therapeutic strategy for cancers which harbor wildtype TP53 expression. Implications: Loss of ANGEL2 contributes to decreased wildtype TP53 translation promoting doxorubicin resistance which can be rescued via an ANGEL2-derived peptide.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}